DE1250828B - Process for the preparation of the spasmolytically active 6,7,3 ', 4' - tetraethoxy-1-benzylidene-1,2,3,4 tetrahydroisoquinoline and its salts - Google Patents
Process for the preparation of the spasmolytically active 6,7,3 ', 4' - tetraethoxy-1-benzylidene-1,2,3,4 tetrahydroisoquinoline and its saltsInfo
- Publication number
- DE1250828B DE1250828B DENDAT1250828D DE1250828DB DE1250828B DE 1250828 B DE1250828 B DE 1250828B DE NDAT1250828 D DENDAT1250828 D DE NDAT1250828D DE 1250828D B DE1250828D B DE 1250828DB DE 1250828 B DE1250828 B DE 1250828B
- Authority
- DE
- Germany
- Prior art keywords
- salts
- tetraethoxy
- tetrahydroisoquinoline
- benzylidene
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- WXWBNUBJVJKZAS-UHFFFAOYSA-N 2-(3,4-diethoxyphenyl)-n-[2-(3,4-diethoxyphenyl)ethyl]acetamide Chemical compound C1=C(OCC)C(OCC)=CC=C1CCNC(=O)CC1=CC=C(OCC)C(OCC)=C1 WXWBNUBJVJKZAS-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- JBFLYOLJRKJYNV-MASIZSFYSA-N (1z)-1-[(3,4-diethoxyphenyl)methylidene]-6,7-diethoxy-3,4-dihydro-2h-isoquinoline;hydron;chloride Chemical compound Cl.C1=C(OCC)C(OCC)=CC=C1\C=C/1C2=CC(OCC)=C(OCC)C=C2CCN\1 JBFLYOLJRKJYNV-MASIZSFYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 5
- 230000002048 spasmolytic effect Effects 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960001789 papaverine Drugs 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- RVVWZHFHRWHWHT-UHFFFAOYSA-N (2,3-dimethoxyphenyl) acetate Chemical compound COC1=CC=CC(OC(C)=O)=C1OC RVVWZHFHRWHWHT-UHFFFAOYSA-N 0.000 description 1
- GIVPQJQIHBLXEL-UHFFFAOYSA-N (4-nitrophenyl) 2-hydroxypropanoate Chemical compound CC(O)C(=O)OC1=CC=C([N+]([O-])=O)C=C1 GIVPQJQIHBLXEL-UHFFFAOYSA-N 0.000 description 1
- FODBVCSYJKNBLO-UHFFFAOYSA-N 2,3-dimethoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1OC FODBVCSYJKNBLO-UHFFFAOYSA-N 0.000 description 1
- YOZILQVNIWNPFP-UHFFFAOYSA-N 2-(4-chlorophenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(Cl)C=C1 YOZILQVNIWNPFP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- TZINJDCZLXCLJD-UHFFFAOYSA-N CCOC1=CC=CC(OC(C)=O)=C1OCC Chemical compound CCOC1=CC=CC(OC(C)=O)=C1OCC TZINJDCZLXCLJD-UHFFFAOYSA-N 0.000 description 1
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IYHWLQXCDRWBRA-UHFFFAOYSA-N OC(=O)O.C1=CC=CC=2OC3=CC=CC=C3CC12 Chemical compound OC(=O)O.C1=CC=CC=2OC3=CC=CC=C3CC12 IYHWLQXCDRWBRA-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
AUSLEGESCHRIFTEDITORIAL
Int. ΟΙInt. ΟΙ
07d07d
Deutsche Kl.: 12 ρ-1/20 German class: 12 ρ -1/20
Nummer: 1 250 828Number: 1 250 828
Aktenzeichen: C 27750IV d/12 ρFile number: C 27750IV d / 12 ρ
Anmeldetag: 18. August 1962 Filing date: August 18, 1962
Auslegetag: 28. September 1967Opening day: September 28, 1967
Es wurde gefunden, daß das bisher unbekannte 6,7,3', 4' -Tetraäthoxy-l-bi&yliden-l, 2,3,4-tetrahydro isochinolin bzw. dessen Salze wertvolle Eigenschaften besitzen, die sich von den für ähnliche Verbindungen bekannten Eigenschaften in mehrerer Hinsicht unterscheiden, und daß diese Verbindung in der Pharmazie verwendet werden kann. Es ist zwar bekannt, daß Verbindungen, die einen Isochinolinring enthalten, allgemein spasmolytische Eigenschaften besitzen. Die erfindungsgemäß erhältliche Verbindung weist jedoch neben ihrer spasmolytischen Wirkung auch noch eine oft erwünschte analgetische, vasodilatorische und blutdrucksenkende Wirkung auf.It has been found that the hitherto unknown 6,7,3 ', 4'-tetraethoxy-1-bi & ylidene-1, 2,3,4-tetrahydroisoquinoline or its salts have valuable properties that differ from those for similar compounds known properties differ in several respects, and that this compound in pharmacy can be used. It is known that compounds containing an isoquinoline ring are general have spasmolytic properties. However, the compound obtainable according to the invention has In addition to its spasmolytic effect, it also has an often desired analgesic, vasodilatory and antihypertensive effect Effect on.
Es wurde ferner gefunden, daß man das 6,7,3',4'-Tetraäthoxy-1 -benzyliden -1,2,3,4-tetrahydroisochinolin und seine Salze nach einem Verfahren herstellen kann, das dadurch gekennzeichnet ist, daß man in an sich bekannter Weise N-(3',4'-Diäthoxyphenyläthyl)-3,4-diäthoxyphenylacetylamid in Gegenwart eines sauren, wasserbindenden Kondensationsmittels bei einer Temperatur unter 100° C, vorteilhaft in Gegenwart eines Lösungsmittels, ringschließend kondensiert und gegebenenfalls das erhaltene Produkt mit einer Säure in eines seiner Salze überführt bzw. "aus einem seiner; Salze mittels Alkalien die freie Base herstellt:It has also been found that 6,7,3 ', 4'-tetraethoxy-1 -benzylidene -1,2,3,4-tetrahydroisoquinoline and its salts can be produced by a process, which is characterized in that N- (3 ', 4'-diethoxyphenylethyl) -3,4-diethoxyphenylacetylamide is used in a manner known per se in the presence of an acidic, water-binding condensing agent at a temperature below 100 ° C, advantageously in the presence of one Solvent, ring-closed condensed and optionally the product obtained with an acid converted into one of its salts or "produces the free base from one of its; salts by means of alkalis:
Bei der Durchführung des erfindungsgemäßen Verfahrens kann als Kondensationsmittel z. B. Phosphoroxychlorid oder Phosphorpentoxyd verwendet werden. Die Reaktion wird zweckmäßig in einem organischen Lösungsmittel, z.B. in Benzol oder, Chloroform, durchgeführt. Nach erfolgter Kondensation wird das Reaktionsgerriisch angesäuert, , worauf das ; überschüssige .Kondensationsmittel (z. B.; Phosphoroxychlorid) durch Zusetzen von Wasser, zersetzt und das Lösungsmittel abgetrieben wird. Die Verbindung wird in diesem Fall in Form des salzsaueren Salzes erhalten, aus dem es gegebenenfalls in die freie Base oder in weitere Salze übergeführt werden kann.When carrying out the process according to the invention can be used as a condensing agent such. B. phosphorus oxychloride or phosphorus pentoxide can be used. The reaction is conveniently carried out in an organic Solvents, e.g. in benzene or chloroform, carried out. After condensation has taken place, the Acidified reaction gerriisch, whereupon that; excess condensation agent (e.g. phosphorus oxychloride) by adding water, decomposes and the solvent is driven off. The connection will in this case obtained in the form of the hydrochloric acid salt, from which it is optionally converted into the free base or in further salts can be transferred.
Das Verfahren gemäß der Erfindung wird durch folgendes -Beispiel erläutert. :, ; r · ;The method according to the invention is illustrated by the following example. : ,; r ·;
. ■■-·"-■■ ' B ei sp i el -!;.· : :. : · - ■■ - · "- ■■ 'T he sp i el!.
104 g ; N-(3',4'-Piäthoxyphenyläthyl)-3,4-diäthoxyphenylacetylamid (F. 108 bis 1090C) wird in 250 ml Benzol 2 Stunden lang in Gegenwart von 50 g Phosphoroxychlorid zum Sieden erwärmt. Hierauf werden etwa 200 bis 220 ml Benzol abgetrieben. Der hellgelbe, dickflüssige Rückstand wird mit 300 ml 96°/^igem Alkohol und 30 ml konzentrierter Salzsäure versetzt. Das1 Reaktionsgemisch erwärmt sieh und wird durch weiteres, Erwärmen zu leichtem Sieden gebracht. Es wird ein Teil der organischen Lösungsmittel fbge-104 g ; N- (3 ', 4'-Piäthoxyphenyläthyl) -3,4-diäthoxyphenylacetylamid (F. 108-109 0 C) is heated in 250 ml of benzene for 2 hours in the presence of 50 g of phosphorus oxychloride to boiling. About 200 to 220 ml of benzene are then driven off. 300 ml of 96% alcohol and 30 ml of concentrated hydrochloric acid are added to the light yellow, viscous residue. The 1 reaction mixture warms up and is brought to a gentle boil by further heating. Some of the organic solvents are
Verfahren zur Herstellung des spasmolytisch
wirksamen 6,7,3',4'-Tetraäthoxy-l-benzyliden-1,2,3,4-tetrahydroisochinolins und seiner SalzeProcess for the preparation of the spasmolytic
effective 6,7,3 ', 4'-tetraethoxy-1-benzylidene-1,2,3,4-tetrahydroisoquinoline and its salts
Anmelder:Applicant:
Chinoin Gyogyszer es Vegyeszeti Termekek ■Chinoin Gyogyszer es Vegyeszeti Termekek ■
Gyära R. T., BudapestGyära R. T., Budapest
Vertreter:Representative:
Dr. G. W. LotterhosDr. G. W. Lotterhos
und Dr.-Ing. H. W. Lotterhos, Patentanwälte,and Dr.-Ing. H. W. Lotterhos, patent attorneys,
Frankfurt/M., Annastr. 19Frankfurt / M., Annastr. 19th
Als Erfinder benannt:
Dipl.-Ing. Chem. Zoltän Meszäros,
Dipl.-Ing. Chem. Dr. Peter Szentmiklosi,
Iren Czibula, BudapestNamed as inventor:
Dipl.-Ing. Chem. Zoltän Meszäros,
Dipl.-Ing. Chem. Dr. Peter Szentmiklosi,
Iren Czibula, Budapest
'~ '" Beanspruchte Priorität:'~' "Claimed priority:
Ungarn vom 30. August 1961 (CI-380),
vom 10. April 1962 (CI-390)Hungary of August 30, 1961 (CI-380),
dated April 10, 1962 (CI-390)
trieben, worauf die heiße Lösung' unter Umrühren abgekühlt wird. Das Produkt scheidet in Form von glitzernden hellgelben Kristallen aus, die filtriert, mitdrifted, whereupon the hot solution 'is cooled while stirring. The product separates in the form of glittering pale yellow crystals that filtered off with
-Alkohol gewaschen und bei 70 bis 809C getrocknet-Alcohol washed and dried at 70 to 80 9 C.
werden. Es werden' 104 bis 105 g 6,7,3',4'-Tetraäthoxy-l-benzyliden-l^^^-tetrahydroisochinolin-hydro- chlorid erhalten, F. 206 bis 2080C. Das Produkt kann aus einem 2- bis 3facheii Volumen an Alkohol um-will. There are '104 to 105 g 6,7,3', 4'-tetraethoxy-l-benzylidene-l ^^^ - tetrahydroisoquinoline hydrochloride obtained, F. 206 to 208 0 C. The product can be obtained from a 2- up to 3 times the volume of alcohol
• kristallisiert werden, worauf 96 g eines bei 210 bis -212° C schmelzenden Produktes erhalten werden.• be crystallized, whereupon 96 g of one at 210 bis -212 ° C melting product can be obtained.
Ähnlicherweise kann auch das Hydrobromid (F. 200 bis 202°C) hergestellt werden. Das Hydrojddid kann,Hydrobromide (mp 200 to 202 ° C) can also be produced in a similar way. Hydroidide can
. aus dem Hydrochlorid oder aus dem Hydrobromid in -•wäßriger Lösung durch Zusetzen von Kaliumiodid gewonnen werden, F. 212 bis 214° C.. from the hydrochloride or from the hydrobromide in - • aqueous solution by adding potassium iodide can be obtained, m.p. 212 to 214 ° C.
Durch Umsetzen mit der entsprechenden Säure oder einem Alkalisalz derselben können z. B. die folgendenBy reacting the same with the corresponding acid or an alkali salt, for. B. the following
. weiteren Salze hergestellt werden:. other salts are produced:
709 649/427709 649/427
Salzsalt
Schmelzpunkt (° C)Melting point (° C)
Die Salze können aus Alkohol umkristallisiert werden.The salts can be recrystallized from alcohol.
Pharmakologische TestergebnissePharmacological test results
Die pharmakologische Untersuchung des salzsauren Salzes ergab die folgenden Ergebnisse: Toxizität: DL50 =s 19,0 mg/kg u.V., 95,0 mg/kg s. c. und über 1000 mg/kg p. o. (bei Mäusen). Bei narkotisierten Katzen zeigte eine 25-mg/kg-Dosis duodenal verabreicht eine starke Depression des Blutdruckes (bei ίο demselben Versuch zeigte 6,7,3',4'-Tetraäthoxy-l-benzylisochinolin selbst bei 400-mg/kg-Dosen keine Wirkung; das bedeutet, daß die duodenale Resorption wesentlich besser ist als im Falle des 6,7,3',4'-Tetraäthoxy-1-benzylisochinolins). In einer Tyrodelösung wurde am Darm von Mäusen beobachtet, daß die spasmolytische Wirkung der Substanz ED50 = 0,056 beträgt (bei ö^S'^'-Tetraäthoxy-l-benzylisochinolin beträgt derselbe Wert 0,108 mg). In Gegenwart von Blutserum beträgt derselbe Wert ED50 = 0,250 mg (bei 6,7,3^4'-Tetraäthoxy-l-benzylisoehinloin0,756mg) H Nachfolgend sind die Resultate von Versuchen an-· gegeben, in denen 6,7,3',4'-Tetraäthoxy-l-benzyliden-1,2,3,4-tetryhydroisochinolin (No-Spa) hinsichtlich seiner pharmakologischen Wirkung mit der aus der deutschen " Patentschrift 1108 223 bekannten Ver-: ·■'. bindung: l-(3',4'-Diäthoxybenzyl)-2-(N-methyl--N-3"!; 4":dimethoxypheiiyl-äthyl-j6-aminoäthyl)-6,7-diäthoxy-1,2,3,4-tetrahydroisochinolin (D-119) und mit Papaverin verglichen wurde. ;The pharmacological investigation of the hydrochloric acid salt gave the following results: Toxicity: DL 50 = 19.0 mg / kg uV, 95.0 mg / kg sc and over 1000 mg / kg po (in mice). In anesthetized cats, a 25 mg / kg dose administered duodenally showed a severe depression of blood pressure (in ίο the same experiment 6,7,3 ', 4'-tetraethoxy-1-benzylisoquinoline showed none even at 400 mg / kg doses Effect; this means that the duodenal absorption is much better than in the case of 6,7,3 ', 4'-tetraethoxy-1-benzylisoquinoline). In a Tyrode solution on the intestines of mice it was observed that the spasmolytic effect of the substance is ED 50 = 0.056 (the same value is 0.108 mg for δ ^ S '^' - tetraethoxy-1-benzylisoquinoline). In the presence of blood serum, the same value is ED 50 = 0.250 mg (with 6,7,3 ^ 4'-tetraethoxy-1-benzylisoehinloin0,756 mg) H The results of experiments are given below in which 6,7,3 ', 4'-Tetraethoxy-l-benzylidene-1,2,3,4-tetryhydroisoquinoline (No-Spa) with regard to its pharmacological effect with the connection known from the German patent specification 1108 223: · ■'. Connection: l- (3 ', 4'-Diethoxybenzyl) -2- (N-methyl-N-3 "!;4" : dimethoxypheiiyl-ethyl-6-aminoethyl) -6,7-diethoxy-1,2,3,4- tetrahydroisoquinoline (D-119) and compared to papaverine.;
Verbindunglink
s. c.s. c.
LD50 mg/kg*LD 50 mg / kg *
p.o.p.o.
S. C.S. C.
i.v.i.v.
P-Q-i.V.P-Q-i.V.
ED60 in Molkonzentration ED 60 in molar concentration
Oberflächenaktivität in din/cm*Surface activity in din / cm *
ΙΟ"5 ΙΟ " 5
10-10-
IO-7 IO- 7
in Molkonzentrationin molar concentration
22,0
13,522.0
13.5
215,0215.0
310,0310.0
340,0340.0
440,0440.0
9,769.76
25,225.2
No-Spa No-spa
Papaverin HCl ..Papaverine HCl ..
* An Albinorattengruppen nach der Litchfield-Wilcoxonschen Methode. ** Nach Issekutz (B. Issekutz sen., »Arch. exp. Path.«, 176, S. 8,1934).* On groups of albino rats using the Litchfield-Wilcoxon method. ** According to Issekutz (B. Issekutz senior, "Arch. Exp. Path.", 176, p. 8, 1934).
14,0
32,614.0
32.6
4,3 · ΙΟ-8 4.3 ΙΟ- 8
3,5 · ΙΟ-8 3.5 ΙΟ- 8
11,0 · ΙΟ-8 11.0 ΙΟ- 8
56,6
52,3
66,156.6
52.3
66.1
60,9
59,2
73,060.9
59.2
73.0
61,7 64,361.7 64.3
Untersuchung der Darmpassage Sonde verabreicht und nach 1 bzw. 5 Stunden er-Bekanntlich wird die Darmpassage von den Spasmo- mittelt, um wieviel Zentimeter die Kohle vom Pylorus lytika vorübergehend verzögert; deshalb wurden die weitergewandert war. Vor dem Versuch wurden die Verbindungen auch in dieser Richtung an weißen Mäuse 24 Stunden hungern gelassen. Die Tiere Mäusen desselben Stammes untersucht. Den Mäusen 50 wurden getötet und bei der Sektion die Passage unterwurde 10°/0ige Carbo medicinalis peroral mit der sucht.Examination of the intestinal passage probe administered and after 1 or 5 hours, as is well known, the intestinal passage is determined by the spasmos by how many centimeters the charcoal from the pylorus lytika is temporarily delayed; therefore, who had wandered on. The compounds were also starved in this direction on white mice for 24 hours prior to the experiment. The animals examined mice of the same strain. The mice were killed 50 and in the section under the passage was 10 ° / 0 owned Carbo medicinalis orally with the studied.
Stunden5
hours
Coecum JLl 11
Coecum
Coecum JLl 11
Coecum
in Zentimeterfrom the stomach
in centimeters
in Zentimeterfrom the stomach
in centimeters
in Zentimeterfrom the stomach
in centimeters
in Zentimeterfrom the stomach
in centimeters
Coecum XiIl
Coecum
Tabelle 3
Am Straubschen HerzenTable 3
At the heart of Straub
Als cardiotoxisch wirkend erwiesen sich in Ringer-Lösung Ringer's solution proved to have a cardiotoxic effect
Mol/ccmMoles / cc
D-119 in der Konzentration 5,8D-119 in concentration 5.8
No-Spa in der Konzentration ... 1,75No-spa in concentration ... 1.75
Nach Zugabe von RinderblutserumAfter adding bovine blood serum
D-119 in der Konzentration 7,0D-119 in concentration 7.0
No-Spa in der Konzentration ... 1,5No-spa in concentration ... 1.5
■ ίο-6 •ίο-5 ■ ίο- 6 • ίο- 5
ΙΟ"5 ΙΟ " 5
•ίο-6 • ίο- 6
Diese Resultate zeigen folgendes:These results show the following:
1. No-Spa wird oral besser resorbiert als D-119.1. No-Spa is better absorbed orally than D-119.
2. Hinsichtlich der Wirkungsstärke besteht zwischen den beiden Verbindungen kein wesentlicher Unterschied; in vitro wirkt zwar D-119 etwas besser, doch wird es stärker an die Serumproteine gebunden als No-Spa.2. In terms of potency, there is no significant difference between the two compounds Difference; In vitro, D-119 works a little better, but it is stronger on the serum proteins bound as a no-spa.
3. Der spasmolytische Effekt (Wirkungsdauer) von D-119 hält zu lange an.3. The spasmolytic effect (duration of action) of D-119 lasts too long.
Claims (2)
Deutsche Auslegeschrift Nr. 1108 223.Considered publications:
German interpretative document No. 1108 223.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US229722A US3337539A (en) | 1962-10-10 | 1962-10-10 | Tetraethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives and salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1250828B true DE1250828B (en) | 1967-09-28 |
Family
ID=22862439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DENDAT1250828D Pending DE1250828B (en) | 1962-10-10 | Process for the preparation of the spasmolytically active 6,7,3 ', 4' - tetraethoxy-1-benzylidene-1,2,3,4 tetrahydroisoquinoline and its salts |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US3337539A (en) |
| DE (1) | DE1250828B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1379111A (en) * | 1972-04-13 | 1975-01-02 | Aspro Nicholas Ltd | Preparation of fused-ring pyridine and pyrazine derivatives |
| FR2426046A1 (en) * | 1978-05-18 | 1979-12-14 | Synthelabo | TETRAHYDRO-ISOQUINOLEINE DERIVATIVE, ITS PREPARATION AND THERAPEUTIC APPLICATION |
| GB8518634D0 (en) * | 1985-07-23 | 1985-08-29 | Smithkline Beckman Corp | Chemical compounds |
| JPS62265266A (en) * | 1986-05-13 | 1987-11-18 | Takasago Corp | Production of n-acyl-tetrahydroisoquinoline compound |
| JP2001518468A (en) * | 1997-09-30 | 2001-10-16 | モレキュラー デザインズ インターナショナル，インコーポレイテッド | β3 adrenergic receptor antagonists, antagonist compounds and methods of application thereof |
| US6593341B2 (en) | 2001-03-29 | 2003-07-15 | Molecular Design International, Inc. | β3-adrenoreceptor agonists, agonist compositions and methods of making and using the same |
| US6596734B1 (en) | 2002-10-11 | 2003-07-22 | Molecular Design International, Inc. | Tetrahydroisoquinoline compounds for use as β3-adrenoreceptor agonists |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2464004A (en) * | 1944-07-24 | 1949-03-08 | Julep Company | Stable quinoline salt for electrolysis |
| GB621917A (en) * | 1945-11-28 | 1949-04-22 | Drammens Jernsta Beri & Mek Va | Improved freezing apparatus |
| US2634272A (en) * | 1950-05-27 | 1953-04-07 | Hoffmann La Roche | 1-benzyl-hexahydroisoquinolines and preparation thereof |
| US2719150A (en) * | 1951-01-16 | 1955-09-27 | Hoffmann La Roche | Process for the manufacture of octahydroisoquinoline derivatives and intermediates therein |
| US2728769A (en) * | 1954-08-17 | 1955-12-27 | Lilly Co Eli | Alkoxybenzylisoquinolines and salts thereof |
| US3020202A (en) * | 1959-07-21 | 1962-02-06 | Upjohn Co | 2-acetamido-4-phenyl thiazole process of inhibiting gastric secretion in human beings |
| US3063902A (en) * | 1961-01-18 | 1962-11-13 | Irwin Neisler & Co | Analgesic aralkyl-pyridines |
-
0
- DE DENDAT1250828D patent/DE1250828B/en active Pending
-
1962
- 1962-10-10 US US229722A patent/US3337539A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US3337539A (en) | 1967-08-22 |
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